ABSTRACT In this proposal, we wish to determine the utility of cutaneous alpha-synuclein (?SN) measured in skin biopsies as a biomarker in the alpha-synucleinopathies with autonomic failure [multiple system atrophy (MSA) and the Lewy body disorders, pure autonomic failure (PAF) and Parkinson's disease (PD)]. This will be accomplished in 3 studies. In the first study, we will determine the cutaneous deposition of ?SN in multiple system atrophy and contrast it with the Lewy body alpha-synucleinopathies with orthostatic hypotension (PD and PAF) in a cross-sectional study and subsequent longitudinal study. We anticipate that individuals with MSA will have lower ?SN deposition in cutaneous skin biopsies than similarly affected individuals with the Lewy body alpha- synucleinopathies (PD and PAF) and orthostatic hypotension assessed in a cross-sectional study, and that low cutaneous ?SN deposition will predict worse prognosis in a longitudinal study. In the second study, we will determine the amount of ?SN in cutaneous autonomic fibers from post-mortem scalp and abdomen skin of pathologically confirmed patients with MSA, PD and healthy and diseased controls. We anticipate that measures of ?SN immunoreactivity in the skin will be greater in patients with PD than patients with MSA, and that ?SN immunoreactivity in PD, but not MSA, will correlate with neuropathological scores and the United Parkinson's Disease Rating Scale scores. In the third study we will determine whether ?SN deposition in the skin is correlated with myocardial noradrenergic innervation as indicated by cardiac sympathetic neuroimaging in the alpha-synucleinopathies with orthostatic hypotension. We anticipate that individuals with MSA will have low ?SN deposition in cutaneous skin biopsies and normal cardiac 6-[18F]fluorodopamine-derived radioactivity, whereas individuals with PD or PAF will have high ?SN deposition and low cardiac 6- [18F]fluorodopamine-derived radioactivity. If successful, the proposed studies will provide a valid diagnostic and prognostic biomarker and be a first step in the development of a surrogate endpoint for disease modifying and neuroprotective therapies in the alpha-synucleinopathy neurodegenerative diseases.